This proposal focuses on the role of CD81 in HCV-induced B cell polyclonal activation and lymphogenesis. Hepatitis C virus (HCV) has been shown to be associated with lymphoproliferative diseases, including cryoglobulinemia and B cell lymphomas. It was recently shown that the cellular ligand for the envelope glycoprotein E2 of HCV is CD81. Our laboratory originally identified CD81 as TAPA-1, target of an surface signaling complex that includes the B cell specific molecules CD19 and CD21. The dual temporal engagement of this complex and the B cell Receptor (BCR) results in a reduced thresholds of activation for B cells. It is of note that CD21 in this complex is the receptor for the Epstein Barr virus (EBV), also known to induce polyclonal B cell activation and B cell proliferative disease. Specific Aim 1 will test whether recombinant HCV 32 glycoprotein shown recently in our lab to bind cellular CD81, is capable of inducing B cell activation. Specific Aim 2 will determine whether any of HCV- associated lymphomas originated in B cells that express a BCR that binds HCV envelope glycoproteins. In Specific Aim 3 we will create a B cell line capable of dual contact with HCV-by binding both to an engineered anti-E2 BCR and to the CD81 molecule. We will then test whether binding of E2 to such a B cell line could indeed induce increased B cell activation by the dual signaling cascades thereby mimicking the hypothesized HCV-induced lymphoproliferation. The proposed experiments should provide insight into HCV-associated lymphomas by determining whether HCV acts as a polyclonal activator of B cells or whether these lymphomas originate in B cells responding specifically to the virus.